Average rates of protein catabolism in diabetes and starvation are increased by 50-150% in insulin-sensitive tissues. Our overall objectives are to study the characteristics and possible causes of this enhanced protein degradation. We have found that several general characteristics of normal protein catabolism are strikingly altered in liver and muscle of diabetic or starved rats indicating that protein degradation in diabetes and starvation may be fundamentally different from basal protein catabolism in normal, well-nourished animals. The enhanced degradation in diabetes and starvation results from more rapid catabolism of proteins that are relatively stable in normal tissues. The increased degradative rates of such proteins are not associated with alterations in protein structure and so must reflect changes in the properties of the degradative machinery within cells. We have begun studies characterizing protein degradation in IMR-90 human lung fibroblasts, and these cells appear to provide an attractive model system for more detailed analyses of protein degradation during deprivation for specific hormones and nutrients. After withdrawal of serum or insulin, overall proteolysis is enhanced and has the characteristics of the enhanced catabolism associated with starvation or diabetes in intact animals. By microinjecting specific radioactive proteins into IMR-90 fibroblasts, we hope to map in detail the mechanisms and pathways of protein degradation in both well-nourished and nutrient-deprived conditions.